In recent years in order to develop medicinal preparations of a new generation for use in the therapy of oncological diseases, an intensive search is being carried out for anticancer agents based on complexes of transition metals with an improved activity spectrum and reduced side effects as compared with already used clinical preparations, for example, cisplatin, sodium nitroprusside and the like.
The use of NO donors as a new class of anticancer agents is associated with the important role of NO in the process of growth of malignant neoplasms [Wink D., Vodovoz J., Cook J., Biochemistry, 1998, 63, 7, pp. 948-957]. Nitric oxide was shown to change the level of apoptosis of the tumor cells, the activity of the p53 gene and neoangiogenesis [Brune B., Schenederhan N., Nitric oxide evoked p53-accumulation and apoptosis, Toxicol Letters, 2003, 193, 2, pp. 19-23], to suppress the activity of a key reparation protein O6-methyl-guanine-DNA-methyl-transferase of mammals [L. Liu, M. Xu-Welliver, S. Kanagula, H. E. Pegg, Inactivation and degradation of O6-alkylguanine-DNA alkyltransferase after reaction with nitric oxide. Cancer Res., 2002, 62, pp. 3037-3043]. However, the currently known synthetic NO-donors of different classes (organic nitrates, diazonium diolates, nitrosothiols and others) are not used as clinical therapeutic agents for treating cancer diseases but they are only used to enhance (to a different degree depending on chemical nature) the effect of existing chemotherapeutic agents or radiotherapy [Wink D., Vodovoz J., Cook J., Biochemistry, 1998, 63, 7, pp. 948-957; N. P. Konovalova, S. A. Goncharova, L. M. Volkova, T. A. Raevskaya, L. T. Eremenko, A. M. Korolev, Nitric Oxide: Biology and Chemistry, 2003, 8, pp. 59-64; Yang, W., Rogers P. A., Ding H., J. Biol. Chem., 2002, 277, pp. 12868-12873; 0. Siri, A. Tabard, P. Pullumbi, R. Guilard, Inorg. Chim. Acta, 2003, 350, p. 633; J. L. Burgaud, E. Jngini, Del Soldato P. Ann, N.Y. Acad. Sci. 2002, 962, p. 360; T. I. Karu, L. V. Pyatibrat, G. S. Kalendo, Toxicology Letters, 2001, 121, p. 57].
On the other hand, in the last 15 years, nitrosyl iron complexes with sulfur-containing ligands have been reliably established as one of the natural forms of natural reservoirs of NO. Such compounds are formed in cells as a result of endogenous NO effect on active sites of non-heme iron-sulfur proteins [Butler A. R., Megson I. I., Chem. Rev., 2002, 102, pp. 1155-1165] and they are cellular NO “depot”. Binding NO to active sites of metal enzymes, in particular to non-heme iron-containing proteins is being extensively studied [Ford P. C., Lorkovic L. M., Chem. Rev., 2002, 102, 993; Hoshino M., Layeran L. E., Ford P. C., Coord. Chem. Rev., 1999, 187, p. 75]. Their synthetic models (Roussin's “red salt” esters) have the following formula [Fe2(SR)2(NO)4], wherein R is Et, t-Bu, (CH2)4—CH3, C6H5F, Ph [T. Thomas, J. H. Robertson, E. G. Cox, Acta Crystallogr., 1958, 11, p. 599; C. Glidewell, M. E. Harman, M. B. Hursthouse, I. L. Johnson, M. Motevalli, J. Chem. Res., 1998, 212, p. 1676; R. E. Marsh, A. L. Spek, Acta Crystallogr., Sect. B. Struct. Sci., 2001, 57, p. 800; C. Jinhua, M. Shaoping, H. Jinling, L. Jiaxi, Chinese J. Struct. Chem., 1983, 2, p. 263; T. B. Rauchfuss, T. D. Weatherill, Inorg. Chem., 1982, 21, pp. 827-830.]. These binuclear diamagnetic sulfur-nitrosyl complexes of μ-S type with R=Alk generate NO upon thermo- or photo-activation [J. L. Bourassa, P. C. Ford, Coord. Chem. Rev., 2000, 200-202, pp. 887-900] and may serve as new promising anticancer NO-donor agents. In the article by A. Janczyk et al. Nitric Oxide, 2004, 10, 1, pp. 42-50, the direct cytotoxic effect of a nitrosyl iron complex Na[Fe4S3(NO)7] on the human and mouse melanoma cells has been studied for the first time. However, this nitrosyl iron complex generates NO upon photoactivation only, and it cannot be used as an anticancer medicament because of the high toxicity with regard to normal cells.
Binuclear paramagnetic sulfur-nitrosyl iron complexes with aromatic ligands of μ-N—C—S type [N. A. Sanina, S. M. Aldoshin, Funktsional'niye modeli nitrozil'nykh [Fe—S] proteinov (“Functional models of nitrosyl [Fe—S] proteins”)// Izv. AN. Ser. Khim. (News of the Academy of Sciences, the Chemical series) (2004), 11, 2326-2345; N. A. Sanina, S. M. Aldoshin, T. N. Rudneva, N. I. Golovina, G. V. Shylov, Yu. M. Shul'ga, V. M. Martynenko, N. S. Ovanesyan, “Sintez, structura I tverdofazniye prevrascheniya nitrizil'nogo complexa zheleza Na2[Fe2(S2O3)2(NO)4].4H2O” (“Synthesis, structure and solid phase conversions of nitrosyl iron complex Na2[Fe2(S2O3)2(NO)4].4H2O”), Koordinatsionnaya Khimiya (Coordination Chemistry), 2005, 31, 301-306; N. A. Sanina, T. N. Rudneva, S. M. Aldoshin, G. V. Shylov, D. V. Korchagin, Yu. M. Shul'ga, V. M. Martynenko, N. S. Ovanesyan, “Influence of CH3 group in 1-methyl-imidazole-2-yl on the properties of binuclear sulfur-nitrosyl iron complex with the ligand of μ-N—C—S type”// Inorganica Chimica Acta (2006), 359, 2, 570-576; N. A. Sanina, T. N. Rudneva, S. M. Aldoshin, A. N. Chekhlov, R. B. Morgunov, E. V. Kurganova, N. S. Ovanesyan, “Sintez, stroeniye i NO-donornaya activnosty paramagnitnogo complexa [Fe2(SC3H5N2)2(NO)4] kak modeli nitrozil'nykh [2Fe-2S] belkov” (Synthesis, structure and NO-donor activity of the paramagnetic complex [Fe2(SC3H5N2)2(NO)4] as a model of nitrosyl [2Fe-2S] proteins”// Izvestiya Akademii nauk. Seriya khimicheskaya (News of the Academy of Sciences, the Chemical series), 1 (2007) 28-34; A. F. Vanin. N. A. Sanina, V. A. Serezhenkov, D. Sh. Burbaev, V. I. Lozinsky and S. M. Aldoshin, Nitric oxide: biology & chemistry 2007, 16, 82-93] which spontaneously generate NO in protonic media are also known, and they have been shown by the recent studies to be useful as highly efficient NO donors in chemotherapy [N. A. Sanina, O. S. Zhukova, Z. S. Smirnova, T. N. Rudneva, G. V. Shylov, S. M. Aldoshin “Biyademiye nitrrozil'niye complexy zheleza s benzagetercyclicheskimi proizvodnymi, sposob ikh polucheniya, donor monooxida azota, pharmacevticheskaya kompozitsiya soderzhashchaya ikh I ikh primeneniye v kachestve protivoopukholevykh lekarstvennykh sredstv” (Binuclear nitrosyl iron complexes with benzazaheterocyclic derivatives, a method for preparing the same, a nitric oxide donor, a pharmaceutical composition comprising the same, and use thereof as anticancer agents)—the application No PCT/RU2007/000286 of 30 May 2007; N. A. Sanina, O. S. Zhukova, S. M. Aldoshin, N. S. Emel'anova, G. K. Gerasimova, “Primenenie tetranitrozil'nogo complexa zheleza s tiophenolom v kachestve protivoopukholevogo lekarstvennogo sredstva i pharmacevticheskiye kompozitsii i nabory soderzhashchiye etot complex” (“Use of tetranitrosyl iron complex with thiophenol as an anticancer agent, and pharmaceutical compositions and kits comprising this complex”)—the application No PCT/RU2007000285 of 30 May 2007]. Their wide clinical use, however, is restrained by their low solubility in water and normal saline solution. Thus, there is need in water-soluble (and thus more bioavailable) anticancer agents with enhanced efficacy and lowered toxicity. In the article [S. A. T. Dillinger, H. W. Schmalle, T. Fox, H. Berke, “Developing iron nitrosyl complexes as NO donor prodrugs”// Dalton Trans., (2007)3562-3571] syntheses of binuclear cationic nitrosyl iron complexes with cystamine having the formula [Fe(NO)2S(CH2)2NH3]2X2 (X=Cl, I); performing reactions in toxic tetrahydrofuran using iron dinitrosyls (Fe(CO)2(NO)2 or {Fe(NO)2I]2) preparable in a multi-step process is required to prepare the main products.
The object of the instant invention is to expand the arsenal of anticancer agents and develop nitrosyl iron complexes-based anticancer agents with improved activity spectrum and decreased side effects, in particular, water-soluble binuclear nitrosyl iron complexes with sulfur-containing aliphatic ligands of natural origin (preferably cystamine, penicillamine) acting as NO-donors and possessing enhanced activity and lowered toxicity.